@article{8a69d242080548b8a5c1dc1555ec8796,
title = "CCL21 expression in β-cells induces antigen-expressing stromal cell networks in the pancreas and prevents autoimmune diabetes in mice",
abstract = "Tumors induce tolerance toward their antigens by producing the chemokine CCL21, leading to the formation of tertiary lymphoid organs (TLOs). Ins2-CCL21 transgenic, nonobese diabetic (NOD) mice express CCL21 in pancreatic β-cells and do not develop autoimmune diabetes. We investigated by which mechanisms CCL21 expression prevented diabetes. Ins2-CCL21 mice develop TLOs by 4 weeks of age, consisting of naive CD4+ T cells compartmentalized within networks of CD45- gp38+CD31- fibroblastic reticular cell (FRC)-like cells. Importantly, 12-week-old Ins2-CCL21 TLOs contained FRC-like cells with higher contractility, regulatory, and anti-inflammatory properties and enhanced expression of β-cell autoantigens compared with nontransgenic NOD TLOs found in inflamed islets. Consistently, transgenic mice harbored fewer autoreactive T cells and a higher proportion of regulatory T cells in the islets. Using adoptive transfer and islet transplantation models, we demonstrate that TLO formation in Ins2-CCL21 transgenic islets is critical for the regulation of autoimmunity, and although the effect is systemic, the induction is mediated locally likely by lymphocyte trafficking through TLOs. Overall, our findings suggest that CCL21 promotes TLOs that differ from inflammatory TLOs found in type 1 diabetic islets in that they resemble lymph nodes, contain FRC-like cells expressing β-cell autoantigens, and are able to induce systemic and antigen-specific tolerance leading to diabetes prevention.",
author = "{Gonzalez Badillo}, {Freddy E.} and Tegou, {Flavia Zisi} and Abreu, {Maria M.} and Riccardo Masina and Divya Sha and Mejdi Najjar and Wright, {Shane H.} and Bayer, {Allison L.} and {\'E}va Korpos and Alberto Pugliese and Molano, {R. Damaris} and Tomei, {Alice A.}",
note = "Funding Information: Acknowledgments. The authors are grateful to Dr. Vickie Zhang (Diabetes Research Institute, University of Miami) for technical assistance, the personnel of the DRI Preclinical Cell Processing and Translational Models Core for their help with islet isolation, transplantation, and management of diabetic mice, the DRI Imaging Core for providing expertise on confocal imaging, and the DRI Histology Core headed by Kevin Johnson for his help with histological processing of all samples. Additionally, the authors thank Dr. William Hulme and the Center for Genome Technology of the John P. Hussman Institute for Human Genomics (University of Miami Miller School of Medicine) for their assistance with RNA sequencing and data analysis. Funding. Funding was provided by philanthropic funds from the Diabetes Research Institute Foundation, a grant from JDRF (2-SRA-2016-316-S-B), a grant from the Iacocca Family Foundation, a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (DK-109929), A.A.T.{\textquoteright}s 2017 provost{\textquoteright}s research award, A.A.T.{\textquoteright}s Biomedical Engineering start-up package, and the European Foundation for the Study of Diabetes (ZUW80166). Duality of Interest. A.A.T. is a co-inventor of intellectual property used in this study and may gain royalties from future commercialization of the technology. No other potential conflicts of interest relevant to this article were reported. Author Contributions. F.E.G.B., F.Z.T., M.M.A., R.M., D.S., M.N., S.H.W., A.L.B., {\'E}.K., R.D.M., and A.A.T. generated data, reviewed and edited the manuscript, and contributed to discussion. F.E.G.B., M.M.A., A.P., and A.A.T. designed the research. A.A.T. wrote the manuscript. F.E.G.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.",
year = "2019",
month = oct,
day = "1",
doi = "10.2337/db19-0239",
language = "English (US)",
volume = "68",
pages = "1990--2003",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "10",
}